Immunomodulation is a developing segment of immunopharmacology. Immunomodulator compounds and compositions, as the name implies, are useful for modulating or regulating immunological functions in animals. Immunomodulators may be immunostimulants for building up immunities to, or initiate healing from, certain diseases and disorders. Conversely, immunomodulators may be immunoinhibitors or immunosuppressors for preventing undesirable immune reactions of the body to foreign materials, or to prevent or ameliorate autoimmune reactions or diseases.
Immunomodulators have been found to be useful for treating systemic autoimmune diseases, such as lupus erythematosus and diabetes, as well as immunodeficiency diseases. Further, immunomodulators may be useful for immunotherapy of cancer or to prevent rejections of foreign organs or other tissues in transplants, e.g., kidney, heart, or bone marrow.
Various immunomodulator compounds have been discovered, including FK506, muramylic acid dipeptide derivatives, levamisole, niridazole, oxysuran, flagyl, and others from the groups of interferons, interleukins, leukotrienes, corticosteroids, and cyclosporins. Many of these compounds have been found, however, to have undesirable side effects and/or high toxicity. New immunomodulator compounds are therefore needed to provide a wider range of immunomodulator function for specific areas with a minimum of undesirable side effects.
Various tumor and cancer related diseases afflict man and animals. The term tumor refers to abnormal masses of new tissue growth which is discordant with the economy of the tissue of origin or of the host's body as a whole. Tumors inflict mammals and man with a variety of disorders and conditions, including various forms of cancer. The seriousness of cancer is well known, e.g. cancer is second only to heart and vascular diseases as a cause of death in man. Tumors are common in a variety of mammals, and the prevention and control of the growth and regression of tumors in mammals is important to man.
Considerable research and resources have been devoted to oncology and antitumor measures, including chemotherapy. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling the growth of tumors and other forms of cancer, further antitumor methods and chemical compositions are needed.
It has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activities. For example, the diterpene commonly known as taxol, isolated from several species of yew trees, is a mitotic spindle poison that stabilizes microtubules and inhibits their depolymerization to free tubulin (Fuchs, D. A., R. K. Johnson [1978] Cancer Treat. Rep. 62:1219-1222; Schiff, P. B., J. Fant, S. B. Horwitz [1979] Nature (London) 22:665-667). Taxol is also known to have antitumor activity and has undergone a number of clinical trials which have shown it to be effective in the treatment of a wide range of cancers (Rowinski, E. K. R. C. Donehower [1995] N. Engl. J. Med. 332:1004-1014). See also, e.g., U.S. Pat. Nos. 5,157,049; 4,960,790; and 4,206,221.
Marine life has been the source for the discovery of compounds having varied biological activities. Some of the United States patents which have issued for such inventions are as follows: U.S. Pat. No. 4,548,814 for didemnins, having antiviral activity, were isolated from a marine tunicate; U.S. Pat. No. 4,729,996 discloses compounds, having antitumor properties, that were isolated from marine sponges Teichaxnella morchella and Ptilocaulis walpersi; U.S. Pat. No. 4,808,590 discloses compounds, having antiviral, antitumor, and antifungal properties, isolated from the marine sponge Theonella sp.; and U.S. Pat. No. 4,737,510 discloses compounds, having antiviral and antibacterial properties, isolated from the Caribbean sponge Agelas coniferin. A number of publications have issued disclosing organic compounds derived from marine sponges, including Scheuer, P. J., Ed. (1978-1983) Marine Natural Products, Chemical and Biological Perspectives, Academic Press, New York; Faulkner, D. J. (1984) Natural Products Reports 1:551-598; Faulkner, D. J. (1986) Natural Products Reports 3:1-33; Faulkner, D. J. (1987) Natural Products Reports 4:539-576; Uemura, D., K. Takahashi, T. Yamamoto, C. Katayama, J. Tanaka, Y. Okumura, Y. Hirata (1985) J. Am. Chem. Soc. 107:4796-4798.
Discorhabdin compounds have been produced from marine sponges as disclosed in U.S. Pat. Nos. 4,731,366 and 4,874,767, and have been discussed in various publications including: Perry, N. B. et al (1986) J Org. Chem. 51:5476; Blunt, J. W. et al. (1987) J Nat. Prod. 50:290; Munro, M. H. G. et al. (1987) Bioorganic Marine Chemistry, Scheuer, P. J., Ed., Verlag Chemie: Heidelberg, Vol. 1, Chapter 4; Kobayashi, J. et al. (1987) Tetrahedron Letters 28:4939; Perry, N. B. et al (1988) Tetrahedron Letters 44:1727; Perry, N. B. et al. (1988) J. Org. Chem. 53:4127; and Cheng et al. (1988) J. Org. Chem. 53:4610.
The present invention, utilizing sponges as a source material, provides the art with new biologically active compounds and new pharmaceutical compositions useful as antitumor and immunomodulatory agents, as well as inhibitors of neurodegenerative processes. The present invention has added to the arsenal of pharmaceutical compounds by the discovery of novel compounds isolatable from extracts of marine sponges of the family Desmacididae.